19-substituted 5alpha-halogen-6beta:19-oxidoandrostanes



United States Patent Claims. (Cl. 260-23955) This application is a continuation-in-part of our copend-ing application Ser. No. 122,657, filed July 10, 1961, now abandoned, by Albert Wettstein et al.

The present invention relates to novel 3:19-dioxygenated Sa-halogen-GB: l9-oxido-androstanes, more especially to compounds of the formula wherein R and R stand for 0x0 or hydrogen together with hydroxy or acyloxy, R stands for hydrogen, 0x0 or hydrogen and hydroxy or acyloxy, R stands for 0x0, [i-hydroxy or B-acyloxy together with hydrogen, lower alkyl, lower alkenyl or lower alkinyl and Hal stands for a halogen atom with an atomic weight above 30, especially for bromine or chlorine.

The acyloxy radicals mentioned above, representing esterified hydroxyl groups, are more especially those of aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids containing at most carbon atoms, such as for example, formic, acetic, propionic, butyric, valeric, trimethylacetic, caproic, oenanthic, decanoic, trifluoracetic, carbonic-monornethylor ethylester, hexahydrobenzoic, cyclopentyl-propionic, phenyl-propionic, be-nzoic or furoic acid. The lower alkyl, alkenyl or alkinyl radicals are such as contain at most 7 carbon atoms, for example methyl, ethyl, nor i-propyl, -butyl, -pentyl, -hexyl or -heptyl, vinyl, allyl, met-hallyl, ethinyl, Z-methyl-ethinyl, 2-chloroethinyl and 2-trifluoromethyl-ethinyl.

The compounds of the present invention are extremely valuable intermediates in a technically important, simple process for the manufacture of l9-nor-androstanes to which class of compounds belong several well known androgenic, anabolic and gestagenic agents as well as ovulation inhibitors such as 19-nor-testosterone and its esters, 17a-methyl-19-nor-testosterone, 17cc ethinyl 19- nor-testosterone, A -3-oxo-l7/3-hydroxy 17oz ethinyl- 19-nor-testosterone.

The l9-nor-androstanes are produced from the 3:19- dioxygenated 5a-halogen-6B:19-oxido-androstanes of the present invention by treating them with zinc and acetic acid at elevated temperature whereby A -19-oxo-androstane or A -androstane-19-acicls are formed. After converting the 3-substituent into a 3-oxo-group (e.g., by hydrolysis of a 3-acyloxy group and oxidation of a S-hydroxy group formed) 19-oxygenated A -3-ketones are obtained from which the angular C-l9-substituent is eliminated in known manner.

Among the 19-oxygenated Six-halogen 65:19- oxidoandrostane of the present invention the following are 3,1?8Al5 Patented Apr. 13, 1965 particularly important. 3,8:11a:l7,8:19 tetrahydroxy-5abromo-6B:19-oxido-androstane and its esters, 35:11az17fl: 19-tetrahydroxy-5a-bromo-6fi:19-oxido 17a methyl androstane, the l9:6fl-lactones of 3516 8:17,8-trihydroxy-5uchloroand -5ocbromo-androstane-19-acid, of 3flz6fl-dihydroXy-5u-chloroand -5a-brom0-17-oxo-androstane-l9- acid and of 35:6/3:17fi-trihydroxy-5a-bromoand -5ozchloro-l7ot-methyl-androstane-19-acid and the corresponding compounds in which some or all of the free hydroxy groups are esterified.

The above lactones are obtained from the corresponding 19-unsubstituted 65:19-oxido-androstanes by oxidation with chromium trioxide in acetic acid at a temperature of 60 to C. The l9-unsubstituted 6flzl9-oxidoandrostanes are obtained either by treating a Six-halogen- 6B-hydroxy-androstane with lead tetraacetate in boiling benzene or cyclohexane for several hours or by reacting a 5a-halogen-6/3-hydroxy-androstane in boiling cyclohexane solution with monovalent, positive iodine preferably in the presence of free iodine and strong visible light for 10 to 90 minutes. The monovalent positive iodine may be obtained from N-iodo-succinimide or from silver acerate and iodine or mercuric acetate and iodine. An especially efficient method for the preparation of the Six-halogen-6 3:19-oxido-androstanes consists in treating a 501- halogen-Gfl-hydroxy-androstane in an apolar solvent, e.g., in boiling cyclohexane solution with lead tetraac'etate and iodine. If ll-oxygenated (especially 1la-acyloxy)-5 xhalogen-6fl-hydroxy-androstanes are treated with lead tetraacetate and iodine under the above defined conditions, 5a-halogen-6B: l9-oxido-19-hydroxy-androstane are formed directly during the reaction. These may be oxidized to 1916B-lactones with chromium trioxide in acetonesulfuric acid at last temperature.

The following examples illustrate the invention. temperatures are given in centigrades.

The

Example 1 (a) A suspension of 22.0 grams of calcium carbonate and 66.0 grams of dried lead tetraacetate in 3.3 liters of cyclohexane is heated to 80 C., 17.6 grams of iodine are added, and the mixture is refluxed and stirred for 20 minutes in the dark. The slightly cooled reaction solution is treated with 11.0 grams of 3B-acetoxy-5a-chloro- GB-hydroxy-l7-oxoandrostane and then refluxed with stirring for 2 hours in daylight. The cooled reaction mixture is filtered, the residue exhaustively washed with absolute ether and the filtrate is washed with sodium thiosulfate solution of 10% strength and with water. Evaporation of the dried solution under vacuum yields 12.1 grams of a crystalline product which, after recrystallization from ether-I-methanol, yields 7.65 grams of 3fi-acetoxy-5mchloro-6fl:19-oxido-17-oxo-androstane melting at 180 to 182 C. The infra-red absorption spectrum of the pure compound contains bands, inter alia, at 5.76, 6.73, 7.35, 8.10, 9.65, 10.60, 10.82, 11.35, 11.67 and 1250a.

(b) A solution of 5 grams of 3fi-acetoxy-5a-chloro- 6,8: l9-oxido-l7-oxo androstane in 100 cc. of glacial acetic acid is treated at to C. within 30 minutes with a solution of 7.5 grams of chromium trioxide in 7.5 cc. of water and 60 cc. of glacial acetic acid. After another 15 minutes the reaction mixture is diluted with water and extracted with methylene chloride. The methylene chlo ride solution is washed with water and then with sodium bicarbonate solution, dried with sodium sulfate and evaporated, to yield 2.2 grams of the 19:65-lactone of 3,8- acetoxy-5a-chloro 6p hydroxy-l7-oxo-androstane-l9- acid which is crystallized by adding ether and freed from any residual oxido compound by recrystallization from alcohol. The pure lactone melts at 198 to 199 C.

'2 o In an identical manner to that outlined in parent application Serial No. 122,657, page 3, lines 6l5, there is prepared From A -3fi:17f5-diacetoxy-androstene the 3 8: 17 ,B-diacetoxy-Sa-chloro-Gfi-hydroxy-androstane melting at 197- 199 From A -3/3-acetoxy-17fi-hydroxy-l7ot-methyl androstene the BB-acetoxy 5a chloro 6,8:17/3 dihydroxy-l7amethyl-androstane melting at 179-181" and From A 3,8:l7/J diacetoxy 170: methyl-androstene the 3flz17fl-diacetoxy 5c: chloro-6fl-hydroxy-fizz-methylandrostane.

Example 2 (a) A mixture of 150 cc. of cyclohexane, 1.0 gram of calcium carbonate, 3.0 grams of lead tetraacetate and 980 mg. of iodine is heated for /2 hour with stirring at 80 C. in the dark. 500 mg. of 3B:17B-diacetoxy-5ctchloro-Gfi-hydroxy-androstane are added and the reaction mixture is refluxed further (l /2 to 2 /2 hours) until it has lost its color. The cooled solution is filtered, the residue is washed with ether, and the filtrate is washed with sodium thiosulfate solution of 10% strength and water, dried and evaporated under reduced pressure. Yield: 620 mg. of amorphous 3fizl7fl-diacetoxy-5achloro-6p:19-oxido-androstane mixed with a small amount of a sparingly volatile oil of aromatic odour; the product is purified on alumina. After crystallization from alcohol the pure compound melts at 160 to 161 C. Its infra-red spectrum contains, in addition to the strong acetate ab- Example 3 When a suspension of 5.0 grams of mercuric acetate and 2.5 grams of 3,8-acetoXy-5a-chloro-6fl-hydroxy-17- oxo-androstane in 100 cc. of carbon tetrachloride is heated to the boil for 16 hours in the dark after the addition of 3.98 grams of iodine and the violet solution is then worked up as described in Example 2, there are obtained 2.72 grams of a crystalline crude product which in the infra-red spectrum shows in the CO area a distinct band at 5.60 1. in addition to the bands of the 17-ketone and the 3-acetate at 580,1 and which consists chiefly of 3,8- acetoxy-5a-chloro-6fi:l9-oxido-17-oXo-androstane. The crude product contains in addition a small quantity of 6,3:l9-lactone of 3fl-acetoxy-5a-chloro-6,6-hydroxy-17- oxo-androstane-19-acid.

Example 4 8.75 grams of lead tetraacetate and 4.0 grams of calcium carbonate are suspended in 200 ml. of carbon tetrachloride. After the addition of 2.0 grams of 3,6!11oc117fitriacetoxy-Sa-chloro-efl-hydroxy-17a-methyl androstane (prepared from A -3-oxo-11a:17/3-dihydroxy-l7a-methylandrostene by acetylation to the llarl7fi-diacetate and enolacetylation to give A -3:lla:l7,6-triacetoXy-17otmethyl-androstadiene, sodium borohydride reduction, reacetylation and addition of hypochlorous acid to the 5 :6-

double bond) and of 2.57 grams of iodine the reactive mixture is stirred and boiled under reflux while irradiat ing with a 500 Watt lamp until the color of iodine disappears (about 30 minutes). The cooled reaction mixture is processed as described in the previous example. The residue (11.2 grams) contains a mixture of the 3,8:11a:17(3 triacetoxy-5a-chloro-6/3:l9-oxido-l7a-methyl-androstane and the 3,8:1lot:17B-triacetoxy-5a-chloro- :l9-oxido-l9-hydroxy-lia-methyl-androstane which is separated by chromatographic on 30 grams of alumina.

What is claimed is:

1. The 19:6,8-lactone of the 3fl-acetoxy-5a-chloro-65- hydroxy-17-oxo-androstane-19-acid.

2. The 19:6B-lactone of the 3,8:l7fl-diacetoxy-5a-chloro-androstane-l9-acid.

3. 3,3I1loc2l7/3 triacetoxy-Soc-chloro-6fl:l9-0xido-17amethyl-19-hydroXy-androstane.

4. 3 19-oxygenated 5tt-halo-6p:19-oxido-androstanes of the formula R2- R: OH

Hal

wherein R stands for a member selected from the group consisting of hydroxy together with hydrogen and acyloxy together with hydrogen, R stands for a member selected from the group consisting of a-hydroxy together with hydrogen, u-acyloxy together with hydrogen and two hydrogen atoms, R; stands for a member selected from the group consisting of oxo, hydrogen together with fi-hydroxy, hydrogen together with e-acyloxy and fl-hydroxy together with a lower alkyl, said acyloxy groups being derived from carboxylic acids having 1 to 15 canbon atoms, and Hal stands for a member selected from the group consisting of chlorine and bromine.

5. 3:19-oxygenated 5fi-halo-6fi:19-oxido-androstanes of the formula References Cited by the Examiner UNlTED STATES PATENTS 3,001,989 9/61 Ringold et al. 260239.57

LEWIS GOTTS, Primary Examiner. 

4. 3:19-OXYGENATED 5A-HALO-6B:19-OXIDO-ANDROSTANES OF THE FORMULA 